81-OR: Hide and Seek—Modulating PDL1 and HLA Class I Expression to Protect Human β-Cells in T1D

Abstract

Introduction and Objective: In type 1 diabetes (T1D), β-cells co-orchestrate their own demise by increasing their visibility to the immune system. The balance between HLA Class I and PDL1 expression is particularly critical: β-cells in T1D overexpress HLA Class I, increasing antigen presentation and immune targeting, but also upregulate PDL1, which promotes immune self-tolerance. Strategies to dissociate these mechanisms may aid development of novel T1D therapies. Methods: To study the misguided immune and β-cell dialogue in a relevant and scalable manner, we established three in vitro islet-immune injury models by culturing spheroids from primary human islets with proinflammatory cytokines, activated peripheral blood mononuclear cells or HLA-A2-restricted preproinsulin-specific cytotoxic T lymphocytes. We then modulated activity or expression of putative targets to investigate their effects on PDL1 and HLA Class I expression, β-cell function, survival and T cell infiltration. Results: In the established models, declining β-cell health manifested as increased basal and decreased glucose-stimulated insulin release, reduced intracellular insulin, loss of the first-phase insulin response and elevated proinsulin-to-insulin ratios. 3D microscopy revealed increased HLA Class I and PDL1 expression, and β-cell death. Extensive T cell infiltration and proinflammatory cytokine secretion confirmed immune activation in co-culture models. Liraglutide and HLA Class I blocking antibodies demonstrated anti-inflammatory and immune-protective effects, serving as controls for future studies. We are currently investigating TYK2-inhibitors and STAT2 knockdown as strategies for decoupling HLA Class I and PDL1 expression and immune protection. Our preliminary results shows TYK2 inhibition can protect islets from proinflammatory cytokine damage. Conclusion: The described biomimetic islet-immune assays provide scalable in vitro tools for studying interventions that can protect the β-cells from the immune-mediated attack that leads to T1D. Disclosure S. Jawurek: None. A.C. Title: None. C. Rufer: None. F. Forschler: Employee; InSphero AG. D.L. Eizirik: Advisory Panel; InSphero. B. Yesildag: Other Relationship; Novo Nordisk, Boehringer-Ingelheim, Eli Lilly and Company, Biomea Fusion, Biosplice Therapeutics, Abata Therapeutics, AstraZeneca, Amgen Inc.